Preparation of pharmaceutical compositions

Abstract

A substantially homogeneous composition for human administration comprises a biologically active lipophilic compound dissolved in or associated with at least one micelle-forming lipid. For example, cyclosporin A is dissolved or dispersed in the mixture of PC and MAPC. The composition may be made by dissolving the lipid material in ethanol, adding the lipophilic compound to the ethanol and removing the ethanol, after which the composition may be formulated for human oral administration.

Description

The present invention relates to the preparation of carriers for lipophilic materials in general. More specifically it relates to the formation of an improved carrier for these compounds which disperses in the presence of the aqueous contents of the gastro-intestinal tract (GI) to form drug-carrying lipid aggregates. The invention is particularly suitable for oral applications but can be readily adapted for other uses. The invention especially relates to novel phospholipid-cyclosporin formulations having improved bio-availability, increased efficacy and reduced toxicity and to a process of manufacture of such formulations.BACKGROUND TO THE INVENTIONCyclosporins are fungal metabolites. They are hydrophobic neutral cyclic peptides and have essentially similar chemical and physical properties. Cyclosporin A (CyA) is representative and is the best known example. It is widely used in organ transplants to prevent rejection and as an immunosupressive agent in the treatment of systemic and ...

AI Technical Summary

Problems solved by technology

This is normally provided in an oral form but may involve intravenous injection when it is necessary to obtain an adequate blood concentration quickly or oral therapy proves ineffective.

Unfortunately, there are two major problems associated with oral therapy.

Firstly, since the drug is lipophilic, its absorption from the GI tract is variable and incomplete, and bioavailability can range from 6% to 60%.

This results in variable or inadequate blood concentrations which can bring about graft rejection and failure Secondly, use of CyA is associated with nephrotoxicity.

This system was found to be inherently thermodynamically unstable.

This formulation thus gave erratic inter- and intra-patient bioavailability.

However, no evidence that the formulation would work in vivo was presented.

However, the drug-free nanoparticles also exhibited immunosupressive activity suggesting that they are unlikely to be a suitable vector for carrying CyA.

This solubiliser frequently gives rise to anaphylatic reactions and is itself known to cause nephrotoxicity exacerbating problems associated with the inherent renal toxicity of CyA.

However, there is less certainty about whether the reduced nephrotoxicity reported with intravenous liposomal formulations is in fact due to altered pharmacokinetics of liposome encapsulated CyA or the non-specific, physical binding of the drug to other lipids present in the system.

Fahr (Pharmaceutical Research, 12, 1189-1198 (1995)), however, dismisses this idea and cites evidence suggesting that high lipid doses tend to bind CyA in blood, thereby minimising the amount of drug available in sensitive organs like the kidney.

There are, however. problems regarding entrapment levels and stability, The charge, nature of the headgroups, and the saturation of the hydrocarbon chains have all been shown to influence the level of entrapment of CyA in liposomes.

This problem is not fully recognised and many of the earlier studies, particularly those in which drug entrapment is measured by the analysis of liposomal pellets obtained by ultracentrifugation and no account is taken of the proportion of non-entrapped drug, tend to cite unrealistically high entrapment values.

This is of importance as it is well known in formulation work that free CyA crystals are not absorbed from the GI tract resulting in poor bioavailability.

In practice, it is this crystallisation process that is the main reason why many liposome formulations perform so badly and do not proceed beyond animal testing.

Even if the formulations described in both the above disclosures have successfully managed to overcome these problems, they would still be exceedingly expensive to produce because of the lipids used, particularly at the high lipid / drug ratios involved, and the relatively complex production processes involved.

In general, technical problems relating to entrapment and stability combined with high production costs have, to date, limited the wider use of liposomes as carriers for drugs.

These products are for lifethreatening conditions and the quantities used are relatively small to justify the high costs of the lpids and the complex manufacturing processes involved.

Although the carrying capacity may be adequate, some compositions can be potentially harmful, particularly if administered in large amounts over a prolonged period.

There are many biologically active compounds where optimum bioavailibilty cannot be expressed because of poor solubility.

Many lipophilic drug candidates do not progress to further clinical evaluation because of the inability to formulate a suitable dosage form that would allow the potential benefits of the compound to be assessed.

The mechanism of uptake of CyA from the micelles formed by such detergents is not known but their strong detergency could potentially damage and alter permeability of the mucosa.

Furthermore, expensive and energy intensive equipment is not required to produce liposomes with well defined characteristics.

Astaxanthine is widely used in aquaculture to confer pigment to fish, but large amounts have to be given because of poor bioavailability.

Some vesicular structures can still be observed by electron microscopy but the method is too insensitive to allow the direct visualisation of spherical micelles.

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